Combination of alpha-2 receptor agonist (clonidin) and anti-muscarinic agent (oxybutynin) for the treatment of sialorrhoea

ABSTRACT

An alpha2 adrenoreceptor agonist eg. clonidine, brimonidine, monoxidine, lofexidine is useful for the treatment of sialorrhoea, administered by the paraungual, sublingual or buccal route. The patient to be treated is also given an anti-muscarinic agent eg. oxybutynin, glycopyrrolate, ipratropium.

This application is a National Stage Application of internationalApplication Number PCT/GB2007/050057, filed Feb. 12, 2007; which claimspriority to Great Britain Patent Application No. 0602857.5, filed Feb.13, 2006 and Great Britain Application No. 0602855.9, filed Feb. 13,2006, all of which are incorporated herein in their entirety.

FIELD OF THE INVENTION

This invention relates to a drug combination and its use in thetreatment of sialorrhoea.

BACKGROUND OF THE INVENTION

Patients with severe neurological dysfunction such as motor deficits(e.g. cerebral palsy, peripheral neuromuscular disease, facialparalysis, Parkinson's disease, severe mental retardation, and otherconditions such as stroke and esophageal cancer) suffer from sialorrhoea(or drooling), which is the unintentional loss of saliva and other oralcontents from the mouth. Drooling is often found in individuals withneurological dysfunction. For example, socially significant droolingoccurs in approximately 10% of patients with cerebral palsy. Persistentdrooling beyond the ages of 3 or 4 years is considered abnormaldrooling. Sialorrhoea results from either a hypersecretion of saliva oran impaired ability to swallow; the latter is a particular problem inpatients with motor dysfunction.

Drooling causes impairment of speech, feeding and swallowing problemsand aspiration. Control of drooling is important in preventing chokingand gagging in persons with posterior drooling. Persons who aremotor-impaired can use the many new electronic assistance aids tocommunicate, navigate and provide more integration and self-sufficiencyin everyday life. Unfortunately for those who drool, many of the aidsare controlled through the mouth or facial manipulations. The droolingmay cause social isolation and inability to use the new devices.

Not only is the drooling annoying and limiting for the person withsialorrhoea, there are problems for the caregivers. Carers must cleanand control the drooling, and remove the drool from the body, clothesand surrounding equipment of the drooler. Additionally, carers must bevery careful about exposure to bodily fluids such as drool.

Thus, it is recognized that sialorrhoea requires medical attention.Current treatment includes administration of anticholinergic agents suchas glycopyrrolate and scopolamine, botulinum toxin injections andsurgery.

Where an anti-sialorrheic effect (reduced saliva secretion) is required,it is appropriate neither to completely impair secretion nor to preventsaliva production in response to food etc. It may be possible to reducethe amount of saliva produced by administering an anticholinergic agent,as demonstrated by the positive effects of glycopyrrolate (tablets) andscopolamine (dermal patch). Although glycopyrrolate is a quaternaryammonium compound with restricted access to the CNS, it is not welltolerated by around 20-25% of patients. Likewise, scopolamine isreasonably tolerated for a few days, but many systemic side-effects areencountered. The saliva produced following administration ofglycopyrrolate or scopolamine is extremely thick and as such isunpleasant.

Clonidine is an α2-adrenoceptor agonist and is primarily used clinicallyas an antihypertensive agent. It acts within the central nervous systemto reduce sympathetic nervous tone to the periphery. Besides loweringblood pressure and heart rate, clonidine also causes pronounced sedationand dry mouth. Clonidine has been shown to be effective in reducingsialorrhoea induced by clozapine (Grabowski, 1992, J. Clin.Psychopharmacol., 12, 69-70; Praharaj et al., 2005, J. Psychopharmacol.,19, 426-428). Clonidine (0.15 mg) has been given per os to 17Parkinson's patients and found to significantly reduce sialorrhoea. Fourof the 17 patients experienced side-effects.

Clonidine is one of many imidazole-type compounds that are usedclinically to treat conditions such as hypertension, sedation as anadjunct to anaesthesia (premedication), muscle spasm (spasticity), andwithdrawal symptoms of opiate and alcohol abuse. Examples of other suchcompounds are rilmenidine, dexmedetomidine, tizanidine, moxonidine andlofexidine. All produce their clinical effects by stimulatingα2-adrenoceptors in the brain and cause sedative side-effects and drymouth.

Sialorrhoea can be a side-effect of the administration of certain drugs.For example, clozapine-induced sialorrhoea has been treated with somesuccess with solutions of the non-selective muscarinic receptorantagonist ipratropium, a quaternary derivative of atropine, giveneither sublingually or intranasally (O. Freudenreich et al., 2004, J.Clin. Psychopharmacol., 24, 98-100; J. Calderon et al., 2000, Int. Clin.Psychopharmacol., 15, 49-52). Freudenreich et al. (2004) gaveipratropium nasal spray (0.03-0.06%) sublingually to 8 patientsreceiving clozapine and who suffered from excessive drooling. Afterseveral weeks of use, a full response was reported in 2 patients and apartial response (symptoms controlled for 2-8 hours) in 5 patients,while 1 patient was a non-responder. One drawback with the ipratropiumsolution is its bitter taste. In addition, an ophthalmic solution ofatropine given sublingually was found to reduce clozapine-indicedsialorrhoea (A. Sharma et al., 2004, Ann. Pharmacother., 38, 1538). In asmall case study, ophthalmic atropine solution was given sublingually topatients with Parkinson's disease and significant decline in salivaproduction was recorded. However, 2 of the 7 patients sufferedhallucinations (H. C. Hyson et al., 2002, Mov. Disorders, 17,1318-1320). Atropine is a non-selective muscarinic antagonist thatexhibits significant central nervous system side-effects. The use ofnon-selective muscarinic antagonists that extensively enter the brainand produce undesirable side-effects should be avoided, particularly inpatients with Parkinson's disease (PD).

Another class of known drugs is of anti-muscarinic agents. A newgeneration of anticholinergic muscarinic antagonists is being developedfor indications such as urinary incontinence, overactive bladder,irritable bowel syndrome or COPD. These compounds include tolterodine,darifenacin, solifenacin, zamifenacin, Ro-3202904 (PSD-506), oxybutynin,trospium, revatropate and tiotropium.

Patients with PD are more prone to confusion and hallucinations,particularly as their disease progresses. Also their blood-brain barriermay become more leaky. They are thus much more prone to worseningconfusion and hallucinations when given an anticholinergic agent. Sleepproblems are also extremely common in PD. α2 agonists promote sleep andtherefore are undesirable in PD. Furthermore, in the more elderlypopulation, cardiovascular problems are much more common, as is,particularly in males, bladder outflow obstruction. α2 agonists would beundesirable for the former and anti-muscarinic agents for both.

SUMMARY OF THE INVENTION

The present invention is based on the finding that a combination of ananti-muscarinic agent and an α2-adrenoceptor agonist is useful in thetreatment of sialorrhoea. The combination can have an improved effectand/or reduced side-effects. The two agents may be administeredtogether, in a single composition, or simultaneously, or sequentially.

Further, if the agonist does not cross the blood-brain barrier or isadministered in such a way that it does not readily enter the CNS or isgiven at such concentration that undesired central effects are not seen,it might be expected to reduce salivary flow by stimulating the negativefeedback of α2-adrenoceptors on cholinergic and sympathetic nervessupplying the salivary glands, without producing centrally mediatedside-effects such as hypotension and sedation. Therefore, theα2-adrenoceptor agonist at least is preferably administered by theparaungual, sublingual or buccal route.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 are each bar charts of saliva secretion following drugadministration, showing the results of experiments reported below.

DESCRIPTION OF PREFERRED EMBODIMENTS

Preferred α2-adrenoceptor agonists for use in the invention areclonidine, apraclonidine, brimonidine, rilmedinide, dexmedetomidine,tizanidine, monoxidine and lofexidine. Preferred anti-muscarinic agentsfor use in the invention are tolterodine, darifenacin, solifenacin,zamifenacin, oxybutynin, trospium, revatropate, tiotropium andRo-3202904 (PSD-506).

Each active agent may be used, according to the invention, in anyappropriate form, e.g. as a salt, hydrate or prodrug. If a chiralmolecule, it may be used as a racemate, as a non-racemic mixture or as asubstantially single enantiomer.

In general, each active agent may be administered in any suitableformulation, by paraungual, sublingual or buccal route. It is preferablyformulated as a gum, spray, pastille, lozenge or dispersible tablet.

The respective active agents may be formulated together in a singledosage form. Alternatively, they may be formulated separately andpackaged together, or they may be administered independently. In certaincases, a patient may be receiving one drug for the treatment of anotherindication; this invention then comprises administering the other drug.

Compositions for use in the invention may be formulated in a mannerknown to those skilled in the art so as to give a controlled release,for example rapid release or sustained release, of the compounds of thepresent invention. Pharmaceutically acceptable carriers suitable for usein such compositions are well known in the art. The compositions of theinvention may contain 0.1-99% by weight of active compound. Thecompositions of the invention are generally prepared in unit dosageform. Preferably, a unit dose comprises the active ingredient in anamount of 0.001 to 100 mg. The excipients used in the preparation ofthese compositions are the excipients known in the art.

Appropriate dosage levels may be determined by any suitable method knownto one skilled in the art. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, rate of excretion, drugcombination and the severity of the condition to be treated. Preferably,the active agent is administered at a frequency of 1 to 4 times per day.A typical daily dosage is 1 to 1000 μg, e.g. 10 to 500 μg.

Compositions for oral administration include known pharmaceutical formsfor such administration, for example lozenges, pastilles, dispersibletablets, powders or granules or as a liquid for spraying into the mouth.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be, for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example cornstarch or alginic acid; binding agents, for example starch gelatin,acacia, microcrystalline cellulose or polyvinyl pyrrolidone; andlubricating agents, for example magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time-delay material such as glycerylmonostearate or glyceryl distearate may be employed.

For oral administration, the composition may be in any form that willrelease the active agent, when held in the mouth, whether for a shorttime or for a matter of hours. It may be malleable andnon-disintegrating, and/or chewable or dispersible. Preferred examplesof such compositions are gums, as well as wafers and dispersible tablets(described above). A flavorant will typically be included. It isparticularly desirable if the flavorant has mucolytic properties. Anexample of such a flavorant is menthol.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose. hydroxypropylmethylcellulose,sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long-chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids, for examplepolyoxyethylene sorbitan monooleate. The aqueous suspensions may alsocontain one or more preservatives, for example ethyl or n-propylp-hydroxybenzoate, one or more colouring agents, one or more flavouringagents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, polyoxyethylene hydrogenated castor oil, fatty acids suchas oleic acid, or in a mineral oil such as liquid paraffin or in othersurfactants or detergents. The oily suspensions may contain a thickeningagent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteningagents, such as those set forth above, and flavouring agents may beadded to provide a palatable oral preparation. These compositions may bepreserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable sweetening, flavouring and colouringagents may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin, or mixtures of these. Suitable emulsifying agents may benaturally occurring gums, for example gum acacia or gum tragacanth,naturally occurring phosphatides, for example soya bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavouring and colouringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be in a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid, find use in the preparation of injectables.

The or each active agent may be administered together with a mucolyticagent such as menthol. Menthol or another oil, e.g. eucalyptus oil, maybe used to make the formulation more palatable.

The following study provides evidence of the utility of the presentinvention.

Study

The study examined the effects of clonidine and oxybutynin on salivaproduction in 9 healthy male volunteers. This was an open-label,non-randomised, two-period, rising dose study.

The subjects were assessed on each dosing occasion for saliva productionpre-dose and 1 h, 2.5 h, 4 h and 6 h post-dose. Vital signs wererecorded at specified times during each study period and adverse eventswere reported throughout.

For each subject, the maximum % reduction in saliva production comparedto placebo was calculated for each dose level. Using this information, amixed effects regression analysis of the % reduction in saliva versusdose with subject as a random effect was performed for both clonidineand oxybutynin. From this model, an approximate ED₃₀ and an ED₅₀ werecalculated. The doses that gave the best approximate reduction of 30%(ED₃₀) in salivary flow was then used as a combination treatment. Themean maximum % reduction in saliva production compared to placebo wasalso plotted by dose.

Results

No severe or serious adverse events were reported. The most commonlyoccurring adverse events were headache and fatigue. There were noclinically significant changes to the biochemistry, haematology orurinalysis results observed during the study. There were no clinicallysignificant changes to the vital signs (including blood pressure),physical examination or 12 lead ECGs observed during the study.

The key observation in this study is based on the Saxon test. See Kohler& Winter, Arthritis Rheum. (1985) 28:1128-32, and Stevens et at, Am. J.Diseases Children (1990) 144:570-571. These results are represented inFIGS. 1 and 2.

The results show a trend towards a reduction in saliva production overtime, following administration of oxybutynin and clonidine alone. Thiseffect was most pronounced following administration of clonidine and wassignificant with increasing dose levels. Likewise, there was a reductionin AUCTs following administration of 50 mcg and 100 mcg clonidine whencompared to placebo. There were no significant effects of dose on salivaproduction following administration of oxybutynin, but the AUCT wasreduced following administration of 10 mg when compared to placebo. Theability of oxybutynin to reduce saliva production was more pronouncedfollowing administration in combination with clonidine. A reduction insaliva production was observed when the AUCT following administration ofplacebo was compared to the AUCT following administration of acombination of (i) 2 mg oxybutynin and 50 mcg clonidine or (ii) 2 mgoxybutynin and 100 mcg clonidine. Likewise, a combination of oxybutyninand clonidine resulted in a significant reduction in the AUCT when 2 mgoxybutynin was compared to a combination of (i) 2 mg oxybutynin and 50mcg clonidine and (ii) a combination of 2 mg oxybutynin and 100 mcgclonidine.

The invention claimed is:
 1. A product comprising a therapeutic amountof the α2-adrenoreceptor agonist clonidine and a therapeutic amount ofthe anti-muscarinic agent oxybutynin, as a combined preparation forseparate, simultaneous or sequential use in the treatment of sialorrhoeawherein the amount of clonidine and oxybutynin is synergisticallyeffective in reducing saliva as compared to clonidine or oxybutynin usedalone.
 2. The product of claim 1 which is formulated as a gum, spray,pastille, lozenge or dispersible tablet.
 3. The product of claim 1wherein the product additionally comprises a mucolytic agent.
 4. Theproduct of claim 1 wherein the product additionally comprises menthol oreucalyptus oil.
 5. The product of claim 1, wherein the amount ofclonidine and oxybutynin is synergistically effective in reducing salivain a dose-saliva reduction relationship.
 6. The product of claim 5,wherein the amount of clonidine is about 30 mcg to about 100 mcg in asingle dose, and the amount of oxybutynin is about 2 mg to about 10 mgin a single dose.